Lipofuscin is a general term to describe lysosomal deposits of insoluble materials that accumulate in the tissues of organisms in the process of aging or due to genetic deficiencies in common hydrophobic clearance mechanisms (e.g. mutations of ABC transporters). In its broadest sense, the accumulation of critical amounts of lipofuscin is pathologic in any tissue, but especially so in the tissues of the CNS where the loss of cell function through lipofuscin is particularly apparent.
Lipofuscin is a lipid rich substance which is found to be accumulated in post mitotic cells of e.g. the brain, the heart, or the retinal pigment epithelium in the eye over a life time. The composition is complex and still under investigation. In the eye, one important and well characterized component of lipofuscin is the flurophore N-retinylidene-N-retinylethanolamine (A2E), a byproduct of the visual cycle. It can be detected histologically by its autofluorescence properties. The origin of lipofuscin in the RPE is still under debate (C J Kennedy, P E Rakoczy and I J Constable, ‘Lipofuscin of the Retinal Pigment Epithelium: A Review’, Eye (London, England), 9 (Pt 6) (1995), 763-771.).
Lipofuscin is particularly formed in tissues with high oxidative stress (A Terman and U T Brunk, ‘Lipofuscin: Mechanisms of Formation and Increase with Age’, APMIS: acta pathologica, microbiologica, et immunologica Scandinavica, 106 (1998), 265-276.). It accumulates progressively over time in lysosomes of post mitotic cells, such as neurons and cardiac myocytes and the retinal pigment epithelium (RPE). The exact mechanisms behind this accumulation are still unclear and may vary in different diseases. Numerous studies indicate that the formation of lipofuscin is due to the oxidative alteration of macromolecules by oxygen-derived free radicals generated in reactions catalyzed by redox-active iron of low molecular weight. Two principal explanations for the increase of lipofuscin with age have been suggested. The first one is based on the notion that lipofuscin is not totally eliminated (either by degradation or exocytosis) even at a young age, and, thus, accumulates in postmitotic cells as a function of time. Since oxidative reactions are obligatory for life, they would act as age-independent enhancers of lipofuscin accumulation, as well as of many other manifestations of senescence. The second explanation is that the increase of lipofuscin is an effect of aging, caused by an age-related enhancement of autophagocytosis, a decline in intralysosomal degradation, and/or a decrease in exocytosis.
One general function of the metabolism is to maintain compounds in solution to allow them to be cleared by solution mechanisms (e.g. urine) or efflux mechanisms as carried out by ABC transporters. For this function, the cell contains enzymes for oxidising and conjugating even lipophilic compounds. However, particularly lipophilic components such as pigments are susceptible to redox reactions which may lead to cross-linking and consequent precipitation. Once precipitated, hydrophobic interactions stabilise the precipitate and thereby present few or no sites where the material can interact with the generally deep reaction pockets of hydrolytic enzymes. Hydrophobic deposits are, in turn, likely to further interact with and precipitate other hydrophobic species. Thus, lipofuscin accumulation represents a stabilised form of hydrophobic detritus that appears inaccessible to normal metabolic clearance by enzymes.
Lipofuscinoses and lipofuscinopathies are, therefore, diseases characterised by high levels of lipofuscin deposits as a result of aging, or metabolic defects. Lipofuscin associated degenerative diseases of the eye have in common that lipofuscin is accumulated in the cells of the RPE. Such diseases include age-related macular degeneration, Stargardt's disease, Best's disease and subpopulations of Retinitis pigmentosa.
In age-related macular degeneration (AMD), early stages with full visual capacity of patients are distinguished from advanced stages with beginning to severe visual impairment. For advanced stages of AMD, atrophic AMD with geographic atrophy and exudative AMD (or synonymous wet, neovascular AMD) with choroidal neovascularization are differentiated. Typically but not in all cases, atrophic AMD occurs in the eye before development of the exudative form. All early stages of AMD and advanced atrophic AMD are usually summarized as dry AMD (see FIG. 1). All stages of AMD are characterized by drusen formation and lipofuscin accumulation in RPE cells. Advanced dry AMD is in addition characterized by the complete and irreversible degeneration of the neuroretina tissue forming sharply demarcated areas of RPE atrophy, the so called geographic atrophy. Geographic atrophy extending to the macula, the area of the retina responsible for visual acuity (FIG. 1), will seriously affect the ability to read, recognize faces or pursue everyday activities such as walking, driving, or shopping. As such, the impact of AMD on quality of life and patient independence can be devastating. In wet AMD, in addition to the characteristics of early AMD and usually also advanced dry AMD, neovascularization takes place.
Stargardt's disease (disease code H35.5 according to ICD-10) is a severe inherited juvenile macular degeneration due to autosomal recessive mutation of the ABCA4 gene or autosomal dominant mutation of the ELOVL 4 gene. It begins in late childhood. Along with progression of the disease, lipid rich deposits (lipofuscin) accumulate in the retinal pigment epithelium (RPE) layer beneath the macula. In advanced Stargardt's disease, the build-up of lipofuscin causes atrophy of the RPE and subsequently the macula supplied by this area of the RPE. At the final stage, Stargardt's disease leads to legal blindness.
Best's disease, also termed vitelliform macular dystrophy or vitelliform dystrophy, is a retinal lipofuscinosis leading to progressive vision loss in the macula. The early-onset form, Best disease, is caused by mutations of the gene encoding the chloride transporter bestrophin, VMD2, and usually appears in childhood, The late-onset form begins in middle age, and tends to be more mild and is associated in ca. 25% of cases with mutations of VMD2 or RDS (peripherin).
Retinitis pigmentosa (RP) is a group of inherited disease of the retina. RP patients develop a degeneration of the photoreceptors and retinal pigment epithelium (RPE) cells. RP culminates in the degeneration of the photoreceptors in the fovea reducing central vision. RP is one of the main causes of acquired blindness in developed countries. Abnormal levels of lipofuscin accumulation are observed in more than one-half of RP patients.
Lipofuscin associated diseases are also found in other tissues. For example, neuronal ceroid lipofuscinoses (NCL) is the general name for a family of at least eight genetically separate neurodegenerative disorders that result from excessive accumulation of lipofuscin in the body's tissues. The neuronal ceroid-lipofuscinoses (NCLs) are characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual loss is a feature of most forms.
The primary cause responsible for Alzheimer's disease (AD) remains unknown. Aβ protein has been identified as the main component of amyloid of senile plaques, the hallmark lesion of AD, but it is not certain whether the formation of extracellular Aβ deposits is the main cause of the series of pathological events in the brain in the course of sporadic AD.
Lipofuscin is a relatively overlooked age-related product and the hypothesis was formulated that its release into the extracellular space following the death of neurons may contribute to the formation of senile plaques. The presence of intraneuronal Aβ, similarities between AD and age-related macular degeneration, and the possible explanation of some of the unknown issues in AD suggest that a contribution of lipofuscin to AD pathology should be considered (Giorgio Giaccone and others, ‘Lipofuscin Hypothesis of Alzheimer's Disease', Dementia and Geriatric Cognitive Disorders Extra, 1 (2011), 292-296 <doi:10.1159/000329544>.). At the same time, negative effects of lipofuscin on e.g. proteasomal system have been established (Annika Höhn and Tilman Grune, ‘Lipofuscin: Formation, Effects and Role of Macroautophagy’, Redox biology, 1 (2013), 140-144 <doi:10.1016/j.redox.2013.01.006>.).
It has been found that tetrahydropyridoethers (THPEs), in particular (7R,8R,9R)-2,3-Dimethyl-8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h] [1,7]naphthyridine (INN Name: Soraprazan) and its salts and related compounds remove natural lipofuscin from RPE cells and can therefore serve as active ingredient in the treatment of AMD degeneration, in particular of dry AMD and Stargardt's disease (EP 2080513 A1). The effect has been observed in healthy monkeys removing naturally accumulated lipofuscin (Sylvie Julien and Ulrich Schraermeyer, ‘Lipofuscin Can Be Eliminated from the Retinal Pigment Epithelium of Monkeys’, Neurobiology of aging, 33 (2012), 2390-2397 <doi:10.1016/j.neurobiolaging.2011.12.009>.), in human RPE cells from aged donors (S. Julien and others, ‘Lipofuscin Can Be Eliminated From Retinal Pigment Epithelium After Drug Treatment’, ARVO Meeting Abstracts, 51 (2010), 481.), and in mice exhibiting a gene defect thought to serve as a model for Stargardt's Disease. However, the mode of action of the THPE compounds was unknown.